Figure 8.

Schematic representation of the possible mechanism of action of metformin and everolimus in QGP-1 and H727 cells. Metformin acts via 5′-AMP-activated protein kinase (AMPK) dependent or independent pathways, leading to mTORC1 complex inhibition. Everolimus inhibits mTOR phosphorylation, but its long-term use is limited by the development of resistance, probably due to the activation of Akt signaling. The combination of metformin and everolimus induces a more potent blockade of mTOR and potentially counteracts the resistance mechanisms triggered by everolimus. (A) In QGP-1 cells metformin did not affect Akt phosphorylation, probably acting through the AIP pathway to decrease mTOR phosphorylation. (B) In H727 cells, metformin decreases Akt phosphorylation to suppress mTOR phosphorylation.